Breast cancer (BC) is a heterogeneous disease in which important associations have been established between different ethnic groups and subtypes of BC. These include the predisposition for premenopausal African Americans to develop aggressive triple negative cancers (tumors that lack expression of ER, PR, or HER2). Recent work by the PI (Badve) amongst others shows that quantifying tumor infiltrating lymphocytes (TILs) in breast cancer is prognostic, even in patients treated with chemotherapy. The immune response in invasive carcinoma is directed against tumor antigens as well as due to stromal damage and release of normally sequestered stromal antigens, whereas they are very likely to be restricted to tumor antigens in ductal carcinoma in situ. In response to PQ-C3, we propose that differences in the immune response genes are the basis of disparate outcomes and will determine the likelihood of invasive cancer development in the early stages of tumorigenesis. We further hypothesize that ethnic differences are critical determinants for the development of immune response profiles and could underpin the health disparities observed in different ethnic groups of breast cancer patients. Preliminary studies performed in collaboration with Singapore General Hospital and Oxford University have shown significant differences in the immune profile of DCIS lesions, which are associated with grade, supporting this hypothesis. To address PQC-3, we will develop ethnically well annotated cohorts of ductal carcinoma in situ (DCIS) patients using ancestry profiles (Aim 1).We further correlate established and novel immune response profiles in in ethnicity annotated cohorts of DCIS with ipsilateral breast events using novel multiplex immuno- fluorescence based- in situ analytic methods to enable colocalization analysis of the immune milieu (Aim 2). In parallel, we will perform novel targeted deep sequencing methods to identify novel immune response profiles in these ethnic cohorts and correlate the likelihood of ipsilateral invasive breast cancer development (Aim 3). Our multinational multidisciplinary team is well equipped to perform the necessary tasks and fully characterize the immune response profiles and correlation to clinical outcomes in early in early stages of breast cancer. At the completion of these studies, we expect to identify immune response profiles associated with the progression of DCIS to invasive cancer that are specific to the each ethnic group. Correlation of these immune profiles with outcome will enable us to use these immune response genes for risk stratification and disease progression in DCIS patients. This will lay the foundation to reduce invasive breast cancer in these populations.